Remote closed-loop titration of decongestive therapy for the treatment of advanced heart failure

ABSTRACT

An apparatus comprises one or more physiological sensing circuits that generate a sensed physiological signal and at least one of the physiological sensing circuits is implantable, a measurement circuit configured to recurrently measure one or more physiological parameters that indicate a status of heart failure of the subject, a comparison circuit configured to compare the one or more physiological parameter measurements to one or more physiological parameter target values, a therapy circuit configured to control delivery of one or more drugs to treat heart failure, and a control circuit in electrical communication with the comparison circuit and the therapy circuit and configured to recurrently adjust delivery of drug therapy according to the comparison of the measured physiological parameters to the physiological parameter targets.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.13/605,397, filed Sep. 6, 2012, now issued as U.S. Pat. No. 8,535,235,which is a continuation of application Ser. No. 13/178,945, filed Jul.8, 2011, now issued as U.S. Pat. No. 8,277,389, which is a continuationof U.S. application Ser. No. 12/703,533, filed Feb. 10, 2010, now issuedas U.S. Pat. No. 8,007,442, which is a continuation of U.S. applicationSer. No. 11/142,851, filed Jun. 1, 2005, now issued as U.S. Pat. No.7,670,298, each of which is hereby incorporated by reference in itsentirety.

TECHNICAL FIELD

This document relates to cardiac rhythm management devices generally,and more particularly to cardiac rhythm management devices that employ asensing device to detect a heart sound and to extract morphological datatherefrom, in order to relate the heart sound to a hemodynamic metric.

BACKGROUND

Cardiac pacemakers generally provide functions including sensingelectrical signals generated by the heart, controlling stimulation ofexcitable tissues in the heart, sensing the response of the heart tosuch stimulation, and responding to inadequate or inappropriate stimulusor response (e.g., dysrhythmia) to deliver therapeutic stimuli to theheart. Some pacemakers employ cardiac resynchronization therapy. Someexisting cardiac pacemakers also function to communicate with anexternal programmer device to support a variety of monitoring,diagnostic and configuration functions.

Certain cardiac pacemakers, defibrillators with pacing and/or cardiacresynchronization therapy (CRT) capabilities, and CRT devices(collectively referred to herein by the term “pacemaker”) include aninternal accelerometer for measuring the level of activity of thepatient (e.g., movement caused by walking around, or by muscletwitches). Such pacemakers process (e.g., filter) the accelerometersignal to reduce noise interfering with the measurement of the patient'smotion-related activity, such as the sounds generated by the heartitself, and then use the processed signals as inputs to one or morealgorithms for generating the signals used to control the stimulation ofthe heart. For example, if the accelerometer indicates that a patient iswalking briskly, the pacemaker may stimulate the heart to beat at afaster rate (often subject to an upper rate limit) than when the patientis at rest.

Pacemakers are typically electrically coupled to a patient's heart by alead system. The lead system may include one or multiple leads that mayprovide electrical contact with one or multiple chamber of a patient'sheart. Some leads may contain an accelerometer at their distal end. Whenimplanted, the accelerometer is located within a patient's heart, andmay detect sounds emitted by the heart. Such a scheme may be used, forexample, to detect an S1 heart sound (an S1 heart sound is the firstsound made by the heart during a cardiac cycle). It is known that an S1heart sound contains data content related to left ventricularcontractility, a characteristic of the heart that reveals the capacityof the myocardium to shorten, and therefore to circulate blood throughthe body. A pacemaker system such as the one described may measure S1heart sounds as a means to gather information about the contractility ofthe patient's heart.

The above-described scheme exhibits certain shortcomings, however. Sucha scheme may lead to the use of two accelerometers—an internalaccelerometer for use in adjusting the pacing rate during instances ofphysical exertion by the patient, and an external accelerometer situatedin the heart for the purpose of monitoring heart sounds. Disposing anaccelerometer on the tip of a lead is costly, and could be avoided if aninternal accelerometer could be used to detect heart sounds with asufficient signal-to-noise ratio to permit extraction of data contentrelated to cardiac performance (such as left ventricular contractility).

SUMMARY

Against this backdrop the present invention was developed. According toone embodiment, an implantable device includes a transducer thatconverts heart sounds into an electrical signal. A control circuit iscoupled to the transducer. The control circuit is configured to receivethe electrical signal, identify an S1 heart sound, and convert the S1heart sound into morphological data that relates to a rate of change ofpressure within a ventricle of a heart. A housing encloses the controlcircuit. The transducer is located in a region in or on the housing.

According to another embodiment, a method includes using a transducerlocated outside of a heart to detect an S1 heart sound. The S1 heartsound is converted into an electrical signal using the transducer.Morphological data is extracted from the electrical signal. Themorphological data relates to a rate of change of pressure within aventricle of the heart.

According to yet another embodiment, a system includes an implantabledevice and an external system. The implantable device includes atransducer located in or on the implantable device. The transducer isconfigured to convert heart sounds into an electrical signal. A firstcontrol circuit is coupled to the transducer, and is configured toreceive the electrical signal. The implantable device also includes afirst interface circuit for communicating with the external system. Theexternal system includes a second interface circuit for communicatingwith the implantable device. A second control circuit is coupled to thesecond interface circuit. The first and second control circuitscooperate to identify an S1 heart sound, and to generate morphologicaldata from the S1 heart sound. The morphological data relates to a rateof change of pressure in a ventricle of a heart.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts data supporting the notion that the S1 heart soundcontains certain data content related to maximum rate of change of leftventricular pressure.

FIG. 2 depicts a method of analyzing accelerometer data to determine amorphological characteristic related to a hemodynamic metric, accordingto some embodiments of the present invention.

FIG. 3A depicts a chart presenting rate of change in left ventricularpressure (y-axis) versus time (x-axis).

FIG. 3B depicts a chart presenting conditioned accelerometer data(y-axis) versus time (x-axis).

FIG. 4 depicts a signal flow scheme that may be used to implement themethod of FIG. 2, according to some embodiments of the presentinvention.

FIG. 5 depicts an exemplary system for performance of the methods andschemes disclosed herein.

FIG. 6 depicts a method of adjusting parameters that influence aprocess, according to some embodiments of the present invention.

FIG. 7 depicts a method of identifying occurrence of a cardiac event,according to some embodiments of the present invention.

FIG. 8 depicts a flow diagram of an example of a method of operating amedical device to provide closed-loop control of titration of an agentfor decongestive therapy, according to some embodiments of the presentinvention.

FIG. 9 depicts a block diagram of portions of an example of a systemthat provides closed-loop control of titration of an agent fordecongestive therapy, according to some embodiments of the presentinvention.

FIG. 10 depicts a block diagram of portions of another example of asystem that provides closed-loop control of titration of an agent fordecongestive therapy, according to some embodiments of the presentinvention.

DETAILED DESCRIPTION

During the course of a cardiac cycle, blood flows from the peripheralvenous system to the right atrium. From the right atrium, blood passesthrough the tricuspid valve to the right ventricle. Blood exits theright ventricle, through the pulmonic valve, into the pulmonary artery,and is directed through the lungs, so that the blood may bereoxygenated. Oxygenated blood from the lungs is drawn from thepulmonary vein to the left atrium. From the left atrium, blood passesthough the mitral valve to the left ventricle. Finally, the blood flowsfrom the left ventricle, through the aortic valve, to the peripheralarterial system in order to transfer oxygenated blood to the organs ofthe body.

As the blood circulates and the various valves open and close (as justdescribed), certain heart sounds are produced. The heart sounds occur ina fixed sequence and are respectively referred to as S1, S2, S3 and S4.

The S1 heart sound is caused by acceleration and deceleration of blood,and closure of the mitral and tricuspid valves. The S1 heart soundgenerated during a given cardiac cycle exhibits morphologicalcharacteristics that relate to the maximum rate of change of pressure inthe left ventricle during the given cardiac cycle. The maximum rate ofchange of pressure in the left ventricle is related to, and may be usedas a proxy measurement for, left ventricular contractility. Leftventricular contractility is important, because it indicates thecapacity of the left ventricle to contract, and therefore to circulateblood through the peripheral arterial system.

Heart sounds can include components of the S1, S2, S3 and S4 heartsounds such as the aortic component of S2 (“A2”), the pulmonarycomponent of S2 (“P2”), or other broadband sounds or vibrationsassociated with mechanical activity of the heart, such as valve closuresor fluid movement (e.g., a heart murmur, etc.).

FIG. 1 depicts data illustrating that the S1 heart sound containscertain data content related to maximum rate of change of leftventricular pressure. FIG. 1 presents a chart having an x-axis and ay-axis. Maximum rate of change of left ventricular pressure for a givencardiac cycle is measured along the x-axis in units of millimeters ofmercury per second (mmHg/s). Median peak-to-peak amplitude exhibited byS1 heart sounds over the past N cardiac cycles is measured along they-axis in units of mG, where N is on the order of 10, for example,between 5 and 25. (One scheme by which “median peak-to-peak amplitude”is determined is discussed below).

To obtain the data presented in FIG. 1, animal testing was performed.During the test, the animal was at rest, and its left ventricularfilling pressure was monitored and determined to be constant. Over aspan of time, a drug known to modify myocardial contractility wasadministered. At intervals, the animal's maximum rate of leftventricular pressure change was measured, and was mated with the medianpeak-to-peak amplitude exhibited by S1 heart sounds over the pastN=approximately 10 (5-25) cardiac cycles, as measured by anaccelerometer located at a point remote from the animal's heart. (Theaccelerometer was located within a cardiac rhythm management deviceimplanted in the animal). Further, the accelerometer data was signalconditioned (discussed below) prior to measurement of the peak-to-peakamplitude. Thus, a given data point on the chart of FIG. 1 is determinedby the maximum rate of left ventricular pressure change during a givencycle, and the median peak-to-peak amplitude exhibited by S1 heartsounds over the past N cardiac cycles.

As can be seen from FIG. 1, the median peak-to-peak amplitude exhibitedover a span of cardiac cycles increases (approximately linearly) withthe maximum rate of left ventricular pressure change. Therefore, bymeasuring the median peak-to-peak amplitude exhibited over a span of Ncardiac cycles, the maximum rate of left ventricular pressure change maybe determined.

Accordingly, FIG. 2 illustrates a method useful in arriving at dataindicative of left ventricular contractility. The example of FIG. 2begins with the reception of raw accelerometer data, as shown inoperation 200. Thereafter, the raw accelerometer data is conditioned(discussed below), for example, to remove noise, respiratory components,and baseline wander (operation 202). The resulting data streamsubstantially represents the sounds emitted by the heart.

This conditioned signal is then processed so as to isolate the S1complex, as shown in operation 204. The result of such a process isdepicted in FIG. 3B. FIG. 3B presents conditioned accelerometer data(y-axis) versus time (x-axis). FIG. 3A presents rate of change in leftventricular pressure (y-axis) versus time (x-axis).

FIG. 3B contains a region identified by a dashed box. The dashed boxidentifies the S1 complex. The process of isolating the S1 complexrefers to identifying a point in time t_(m) at which the S1 complexbegins and a point in time t_(n) at which the S1 complex ends.

Returning to FIG. 2, after isolation of the S1 complex at operation 204,peak values are extracted at operation 206. For example, the exemplaryisolated S1 complex depicted in FIG. 3B contains a global maxima labeled“Max,” and a global minima labeled “Min.” The minima and maxima are“global” over the span of time between t_(m) and t_(n). The combinedresult of operations 200-206 is that, for each cardiac cycle, theamplitude values at each global maxima and minima exhibited by an S1heart sound are extracted and stored in a manner to preserve theirrelationship to the cardiac cycle from which they were extracted.

Next, in operations 208 and 210, the median minima and the median maximaexhibited over the last N cardiac cycles are found. For example,assuming that the peak values had been extracted from the J^(th) cardiaccycle in a given instance of execution of operation 206, then operations208 and 210 yield the median minima and the median maxima exhibited overcardiac cycles J−N+1 through J.

Finally, in operation 212, the median minima determined in operation 208is subtracted from the median maxima determined in operation 210. Theresult of operation 212 is an example of a “medianpeak-to-peak-amplitude,” as referred to above with reference to FIG. 1.

FIG. 4 depicts a signal flow scheme that may be used to implement themethod of FIG. 2. As can be seen from FIG. 4, raw accelerometer data issupplied to both a bandpass filter 400 and a baseline estimator 402. Thebandpass filter 400 is characterized by upper and lower cutofffrequencies that are set to pass frequency content included in heartsounds. In one example, the lower and upper cutoff frequencies areapproximately 10 Hz and 50 Hz, respectively. The cutoff frequencies arealso set to reject frequency content due to movement of the patient(e.g., walking or muscular twitching), and to pass frequency content ofthe heart sounds.

Typically, the upper and lower cutoff frequencies of a bandpass filter(such as bandpass filter 400) are determined by two sets of poles. Afirst set of poles determines the lower cutoff frequency (e.g.,placement of poles at 10 Hz generates a lower cutoff frequency atapproximately 10 Hz). Similarly, a second set of poles determines theupper cutoff frequency (again, placement of poles at 50 Hz generates anupper cutoff frequency at approximately 50 Hz). In order to yield anarrow passband region, the sets of poles determining the upper andlower cutoff frequencies may be oriented in proximity to one another(i.e., the poles may be “squeezed” together). Unfortunately, such anapproach tends to exhibit a drawback: the filter may ring when driven bysignals with sharp transitions. Since S1 heart sounds tend to exhibitsharp transitions, the bandpass filter 400 may ring if its passband isnarrowed by way of “squeezing” its poles close together.

To address the problem of ringing, the baseline estimator 402 isintroduced. The baseline estimator 402 yields an estimate of alow-frequency baseline upon which the heart sounds in the accelerometerdata are riding. For example, baseline estimator 402 may be anexponentially-weighted historical averaging unit. By subtracting thebaseline estimate yielded by the estimator 402 from the output of thebandpass filter 400 (using the subtracting unit 404), unwantedlow-frequency content is removed from the signal passed by the filter400. This means that the lower cutoff frequency of the filter 400 may berelaxed (i.e., set at a relatively lower frequency), and that thecombined functioning of the baseline estimator 402 and subtraction unit404 will remove low frequency content. By relaxing the lower cutofffrequency of the filter, the frequency space between the sets of polesmay also be broadened, diminishing the likelihood of ringing in thefilter 400.

The combined functioning of passband filter 400, baseline estimator 402,and subtraction unit 404 operate to achieve the effect described withreference to operation 202 in FIG. 2. Thus, the signal yielded bysubtraction unit 404 primarily includes content related to heart sounds.

The signal from the subtraction unit 404 is passed to an S1 isolatorunit 406, which functions to achieve the result described with referenceto operation 204 in FIG. 2. An exemplary method for automaticallyprocessing accelerometer signals to isolate S1, S2, and S3 heart soundsis disclosed in U.S. Pat. No. 5,792,195, issued to Carlson et al. onAug. 11, 1998, which is incorporated by reference herein in itsentirety.

The output of the S1 isolator unit 406 is a set of time-sequenced datarepresenting an S1 heart sound. Such data is passed to a minima/maximaextractor 408 to find the global minima and maxima of the S1 complex, asdescribed with reference to operation 206 in FIG. 2.

Finally, the output of the minima/maxima extractor 408 is passed to amedian calculator 410 to find the median minima and median maximaexhibited by the last N S1 heart sounds, as described with reference tooperations 208 and 210 in FIG. 2.

Returning briefly to FIG. 1, a formula presented therein describes alinear regression of the data contained in the graph. (In the case ofthe data presented in FIG. 1, the formula is y=0.00009x−0.0625). The“reliability” of the linear regression is indicated by R², which is ameasure of the variance explained by the regression model (in the caseof the data presented in the graph of FIG. 1, R²=0.9866). In oneexample, the reliability of the data is improved (and therefore thereliability of the linear regression model, as understood by R² isimproved) by performing the data processing schemes of FIGS. 2-4 uponheart sounds obtained during periods of exhalation; accelerometer dataobtained from heart sounds occurring during periods of inhalation isignored. To distinguish periods of exhalation and inhalation,transthoracic impedance may be examined (transthoracic impedance maydecrease during exhalation, for example).

FIG. 5 depicts an exemplary system useful for detecting S1 heart sounds,and extracting therefrom one or more morphological characteristicsrelated to left ventricular contractility.

In FIG. 5, an exemplary system 500 for detecting and processing heartsounds includes an implantable system 502 and an external system 504.The implantable system 502 and external system 504 are configured tocommunicate via a communications link 506.

The implantable system 502 includes an implantable device 508operatively coupled to a patient's heart by a lead system 512. Thecomponents of the implantable device 508 include an atrial senseamplifier 514, a ventricular sense amplifier 516, an atrial stimulatingcircuit 518, a ventricular stimulating circuit 520, a control circuit orcontroller 522, a memory 524, an accelerometer 526, an analogpre-processing circuit 528, an analog-to-digital (A/D) converter 530,and an input/output (I/O) interface 532. The components of implantabledevice 508 are housed within an implantable housing (indicated by thebroken lined box in FIG. 5), which may be implanted within the patient'schest cavity (e.g., in the pectoral region) or elsewhere.

The atrial sense amplifier 514, ventricular sense amplifier 516, atrialstimulating circuit 518 and ventricular stimulating circuit 520 areoperatively coupled to lead system 512 via a pair of conductors 534. Thelead system 512 may include an atrial sensing electrode and an atrialstimulating electrode adapted to be disposed in the right atrial chamberof heart and a ventricular sensing electrode and a ventricularstimulating electrode adapted to be disposed in the right ventricularchamber of the heart.

Sensed atrial and ventricular electrical signals generated by thesensing electrodes are applied to the atrial and ventricular senseamplifiers 514 and 516, respectively. Similarly, atrial and ventricularstimulating signals generated by the atrial and ventricular stimulatingcircuits 518 and 520 are applied to the atrial and ventricularstimulating electrodes, respectively. The atrial sense amplifier 514,ventricular sense amplifier 516, atrial stimulating circuit 518, andventricular stimulating circuit 520, are each also operatively coupledto the controller 522.

In other embodiments, other sensing electrode configurations are usedfor internally sensing one or more electrical signals of heart. In oneexample, only one sensing electrode may be used. Alternatively, one ormore electrodes placed within the body but outside of the heart are usedfor sensing cardiac electrical signals. In yet another example, asensing electrode is placed on the implantable housing. In each of theseexamples, the sensing electrodes are operatively coupled to thecontroller 522.

In the embodiment shown in FIG. 5, the sensing electrodes and thestimulating electrodes are disposed in the right side of heart. In otherembodiments, one or more sensing electrode(s) and one or morestimulating electrode(s) are disposed in the left side of the heart (inlieu of being disposed in the right side of the heart, or in addition tosensing electrode(s) and stimulating electrode(s) disposed in the rightside of the heart). The addition of left heart sensing mayadvantageously allow for the resolution of ambiguities due todisassociation of right and left heart conduction.

The controller 522 can include a microcontroller or microprocessor whichcan be configured (e.g., by executing a program stored in a read-onlymemory (ROM) portion of a memory unit 524 and reading and writing datato and from a random access memory (RAM) portion of the memory unit 524)to process the atrial and ventricular electrical signals from the atrialand ventricular sense amplifiers 514 and 516, and to provide controlsignals to the atrial and ventricular stimulating circuits 518 and 520.In response, the stimulating circuits 518 and 520 provide stimulatingpulses to heart via atrial and ventricular stimulating electrodes atappropriate times. In other embodiments, the controller 522 may includeother types of control logic elements or circuitry to perform thefunctions described herein.

The implantable device 508 may be referred to as a dual-chamberpacemaker since pacemaking functions are provided to both atrial andventricular chambers of heart. In another embodiment, the implantablesystem includes a single-chamber pacemaker that senses electricalsignals and provides stimulating pulses to a single chamber of heart. Inyet another embodiment, the implantable system does not provide anystimulation of heart tissues, but includes one or more sensingelectrodes for sensing one or more electrical signals of heart, and forproviding corresponding sensed signals to controller 522. In stillanother embodiment, the implantable system does not provide any sensingelectrodes for sensing any cardiac electrical signals, but is configuredto sense and transmit signals representing heart sounds using a sensorsuch as the accelerometer 526, as described below.

In the remainder of this description, the implantable device 508 isdescribed as a dual-chamber pacemaker for the sake of illustration. Itis to be understood, however, that implantable system 502 need notprovide the stimulation functions described herein, and may provideother functions which are not described herein.

In some embodiments, a minute ventilation output channel and a minuteventilation input channel may be interposed between the controller 522and the ventricular lead. The minute ventilation output channelgenerates a high-frequency, low-voltage signal that is transmitted fromthe ventricular lead (in either unipolar or bipolar mode). The inputchannel receives and conditions the signal. The content of theconditioned signal reveals respiration information.

An accelerometer 526 may be configured to provide sensed signals to theanalog pre-processing circuit 528, which generates an analog outputsignal which is digitized by A/D converter 530. The digitizedaccelerometer signal is received by the controller 522. In theembodiment of FIG. 5, the accelerometer 526 is located within thehousing of implantable device 508. In another embodiment, theaccelerometer 526 is located on the housing of the implantable device.The accelerometer 526 may include, for example, a piezo-electric crystalaccelerometer sensor of the type used by pacemakers to sense the levelof activity of the patient, or may include other types ofaccelerometers. To detect heart sounds, other types of sound-detectingsensors or microphones may also be used, such as a pressure sensor or avibration sensor configured to respond to sounds made by the heart.

In another embodiment, the system 500 includes two or moresound-detecting sensors. In such an embodiment, the plurality of sensedheart sound signals from the plurality of sensors may be individuallytransmitted to external system 504 for display as individual traces, maybe combined (e.g., averaged) by external system 504 before beingdisplayed as a single trace, or may be combined by controller 522 beforebeing transmitted to external system 504 as a single heart sound signal.These sensors may include different types of sensors, sensors that arelocated in different locations, or sensors that generate sensed signalswhich receive different forms of signal processing.

In one embodiment, the accelerometer 526 is configured to generatesensed signals representative of two distinct physical parameters: (1)the level of activity of the patient; and (2) the heart sounds generatedby heart. Accordingly, the analog pre-processing circuit 528 isconfigured to pre-process the sensed signals from the accelerometer 526in a manner which conforms to the signal characteristics of both ofthese physical parameters. For example, if the frequencies of interestfor measuring the patient's level of activity are below 10 Hz, while thefrequencies of interest for detecting heart sounds are between 0.05 Hzand 50 Hz, then analog pre-processing circuit 528 may include a low-passfilter having a cutoff frequency of 50 Hz. The controller 522 may thenperform additional filtering in software, as described above withreference to FIGS. 2-4, for example. Along with filtering, analogpre-processing circuit 528 may perform other processing functionsincluding automatic gain control (AGC) functions.

The analog pre-processing circuit 528 may perform the filtering andbaseline wander removal functions described with reference to operation202 (FIG. 2) and may include modules 400, 402, and 404 (shown in FIG.4). Alternatively, the analog pre-processing circuit 528 may simplyprovide automatic gain control functionality.

In some embodiments, the controller 522 performs one or more of steps204-212 (FIG. 2), and may include one or more of modules 406-410 (FIG.4). In the context of an embodiment in which the analog pre-processingcircuit 528 performs only automatic gain control, the controller mayperform operations 200 and 202 (FIG. 2), and may include modules 400-404(FIG. 4). As discussed below, any operations 200-212 or modules 400-410to be performed digitally by a controller may be performed cooperativelyby the controller 522 within the implantable device 508 and anothercontroller. For example, the controller 522 in the implantable device508 may perform operation 204, and communicate the result to an externalcontroller (contained in a programmer, for example) that performsoperation 206-212. Alternatively, an external controller may perform allof the operations 200 described in FIG. 2.

In another embodiment, the implantable device 508 has two pre-processingchannels for receiving sensed signals from accelerometer 526. In stillanother embodiment, implantable device 508 includes two accelerometers,with one accelerometer configured to generate sensed signalsrepresentative of the level of activity of the patient and the otheraccelerometer configured to generate sensed signals representative ofheart sounds. In these latter two embodiments, any hardware and/orsoftware processing performed on the sensed signals can conform to thespecific characteristics of the respective sensed signals. For example,the analog pre-processing circuit used for the level-of-activity sensedsignals can provide a low-pass filter with a cutoff frequency of 10 Hz,while the analog preprocessing circuit for the heart-sound sensedsignals can provide a band-pass filter with cutoff frequencies of 0.05and 50 Hz. In the latter case, each accelerometer can be selected,located and/or oriented to maximize the detection of the respectivephysical parameter. In yet another embodiment, if the implantable devicedoes not need to sense the level of activity of the patient, theaccelerometer 526 may measure only the sounds made by heart.

The controller 522 is capable of bi-directional communications with anexternal system 504 via an I/O interface 532. In one embodiment, the I/Ointerface 532 communicates using RF signals, which may be understood toinclude inductive coupling. In other embodiments, the I/O interface 532communicates using optical signals, or a combination of RF and opticalsignals (e.g., RF signals for receiving data from the external system504 and optical signals for transmitting data to external system 504, orvice-versa). The controller 522 uses the I/O interface 532 forbi-directional communications with the external system 504 to supportconventional monitoring, diagnostic and configuration pacemakerfunctions. The controller 522 may also use the I/O interface 532 totelemeter data representative of the heart sounds sensed byaccelerometer 526 to the external system 504. In various embodiments,the controller 522 further uses the I/O interface 532 to telemeter datarepresentative of cardiac electrical signals (i.e., electrogram or EGMsignals), which may include data representative of atrial electricalsignals, sensed by the atrial sensing electrode, and/or datarepresentative of ventricular electrical signals, sensed by theventricular sensing electrode. Thus, implantable system 502 is capableof sensing heart sounds, atrial electrical signals and ventricularelectrical signals, and of telemetering data representative of the heartsounds and/or cardiac electrical signals to external system 504. Inother embodiments, the controller 522 telemeters data representative ofcardiac electrical signals which were sensed by other configurations ofinternal cardiac sensing electrodes.

The external system 504 may include an external device 542. The externaldevice 542 may include an external controller 546, an I/O interface 548,user input device(s) 550, and user output device(s) 552. Using the I/Ointerface 548, the external controller 546 is configured forbi-directional communications with the implantable device 508, forreceiving input signals from input device(s) 550, and for applyingcontrol signals to output device(s) 552. The input device(s) 550 includeat least one input device which allows a user (e.g., a physician, nurse,medical technician, etc.) to generate input signals to control theoperation of external device 542, such as at least one user-actuatableswitch, knob, keyboard, pointing device (e.g., mouse), touch-screen,voice-recognition circuit, etc. The output device(s) 552 include atleast one display device (e.g., CRT, flat-panel display, etc.), audiodevice (e.g., speaker, headphone), or other output device whichgenerates user-perceivable outputs (e.g., visual displays, sounds, etc.)in response to control signals. The external controller 546 may beconfigured to receive the data representative of heart sounds, atrialelectrical signals and/or ventricular electrical signals fromimplantable system 502, and to generate control signals that, whenapplied to output device(s) 552, cause the output device(s) to generateoutputs that are representative of the heart sounds, the atrialelectrical signals and/or the ventricular electrical signals.

The external controller 546 may cooperate with the internal controller522 to perform any or all of the steps in FIG. 2. For example, theimplantable device 508 may telemeter conditioned accelerometer data(yielded from operation 202 in FIG. 2) to the external controller 546via the communication link 506. The external controller 546 may performoperations 204-212 upon the telemetered data.

In one embodiment, the system 500 further includes a remote system 554operatively coupled to communicate with the external system 504 viatransmission media 556. The remote system 554 includes one or more userinput device(s) 558, and one or more user output device(s) 560, whichallow a remote user to interact with remote system 554. The transmissionmedia 556 includes, for example, a telephone line, electrical or opticalcable, RF interface, satellite link, local area network (LAN), wide areanetwork (WAN) such as the Internet, etc. The remote system 554cooperates with external system 504 to allow a user located at a remotelocation to perform any of the diagnostic or monitoring functions thatmay be performed by a user located at external system 504. For example,data representative of heart sounds and/or cardiac electrical signalsare communicated by the external system 504 to the remote system 554 viathe transmission media 556 to provide a visual display and/or an audiooutput on the output device(s) 560, thereby allowing a physician at theremote location to aid in the diagnosis of a patient. The system 554 is“remote” in the sense that a user of remote system 554 is not physicallycapable of actuating input device(s) 550 and/or of directly perceivingoutputs generated by output device(s) 552. For example, the system 554may be located in another room, another floor, another building, anothercity or other geographic entity, across a body of water, at anotheraltitude, etc., from the external system 504.

Although not depicted in FIG. 5, the I/O interface 532 may establish acommunication link with a communication device in physical proximity tothe patient. For example, the I/O interface may establish a data linkwith a personal digital assistant, and may upload or download any of thedata mentioned previously or hereafter. The personal digital assistantmay, in turn, establish a link with an access point, so that the linkmay be effectively extended over a network, such as the Internet.

To this point, the disclosure has discussed schemes for detecting aheart sound, generating morphological data from the heart sound, andrelating the morphological data to a hemodynamic metric (FIGS. 1-4). Thedisclosure has also discussed an exemplary device and system forperforming such acts (FIG. 5). The remainder of the disclosure relatesto methods which may make use of the methods discussed with reference toFIG. 1-4, and may make use of the exemplary device or system disclosedwith reference to FIG. 5.

FIG. 6 depicts a method of adjusting parameters that influence aprocess. Any of the acts depicted in FIG. 6 may be performed by anycontroller in the exemplary system of FIG. 5. The method begins withperforming a process known to affect a characteristic of the heart thatinfluences sound, as shown in operation 600. For example, operation 600may include titration of a drug known to influence a heart sound. Aninotrope, for instance, enhances the inotropic state of the heart,resulting in greater myocardial contractility, which influences the S1heart sound (as shown in FIG. 1). Alternatively, operation 600 mayinclude administration of therapy to the heart. For instance, animplantable device (such as the one shown in FIG. 5) may administercardiac resynchronization therapy to the heart. Over time, cardiacresynchronization therapy may make the heart stronger, resulting ingreater myocardial contractility. Again, contractility is known toinfluence the S1 heart sound.

Next, in operation 602, the heart sounds are detected using anaccelerometer that is located at a point that is remote from the heart(e.g., within an implantable device, such as the one depicted in FIG.5). The monitoring operation 602 may include, for example, performingthe acts discussed with reference to FIGS. 2-4. Thus, the medianpeak-to-peak amplitude exhibited by S1 heart sounds may be monitored(after being conditioned, as discussed with reference to FIGS. 2-4) toobtain information regarding the contractility of the left ventricle.

After monitoring the heart sounds in operation 602, it is determinedwhether the cardiac characteristic known to relate to the heart sound isin the desired state. For example, in the context of monitoring S1 heartsounds during administration of cardiac resynchronization therapy, thegoal may be to increase or maximize contractility of the heart byadministration of such therapy. Accordingly, operation 604 may involve adetermination of whether the contractility of the heart has beenmaximized or sufficiently increased. If it is determined that the givencardiac characteristic (e.g., contractility) is, indeed, in the desiredstate, then the process may come to an end, as shown in operation 606.On the other hand, if the desired state has not been reached thencontrol may be passed to operation 608.

Operation 608 is optional. In operation 608, one or more parametersinfluencing execution of the process of operation 600 are changed. Forexample, if operation 600 involved administration of cardiacresynchronization therapy, then one or more resynchronization parametersmay be changed in operation 608. For example, an atrioventricular pacingdelay parameter, biventricular delay parameter, electrode site selectionparameter, etc. may be altered. Execution of operation 608 may beperformed automatically by an implanted cardiac rhythm managementdevice. Alternatively, it may be performed automatically by an externalprocessor (e.g., accelerometer data is telemetered to a programmer orother external device; the accelerometer data is processed according toFIG. 2; the programmer automatically determines how to adjust one ormore parameters on the basis of such processing, and new parameters aretelemetered to the implantable device). Operation 608 may be performedmanually as well (e.g., accelerometer data is telemetered to aprogrammer; the accelerometer data is processed according to FIG. 2; ahealth care professional analyzes the accelerometer data to determinehow to adjust one or more parameters, and new parameters are telemeteredto the implantable device). After execution of operation 608, controlreturns to operation 600, and the controlled process continues.

Operation 608 may be omitted entirely. For example, in the context oftitration, rather than increasing or decreasing the titration rate inoperation 608, the titration rate may remain constant, meaning thatcontrol returns to operation 600 and titration simply continues.

Thus, in sum, the loop defined by operations 600, 602, 604, and 608,functions to monitor and control a process, until a cardiaccharacteristic is observed (by virtue of detection of heart sounds witha remote accelerometer) to be in a desired state.

FIG. 7 depicts a method of identifying an occurrence of a cardiac event.Any of the acts depicted in FIG. 7 may be performed by any controller inthe exemplary system of FIG. 5. The method begins with detecting heartsounds using an accelerometer that is located at a point that is remotefrom the heart (e.g., within an implantable device, such as the onedepicted in FIG. 5), as shown in operation 700. The monitoring operationof operation 700 may include, for example, performing the acts discussedwith reference to FIGS. 2-4. Thus, the median peak-to-peak amplitudeexhibited by S1 heart sounds may be monitored (after being conditioned,as discussed with reference to FIGS. 2-4) to obtain informationregarding the contractility of the left ventricle.

Thereafter, control may be passed to operation 702. Operation 702 isoptional, and may be omitted altogether. In operation 702, theinformation obtained by monitoring of heart sounds in operation 700 iscombined with other information (e.g., exertion level as indicated byrate of respiration and/or motion-related acceleration, etc.). The heartsound information may be combined with any of the information normallymeasured by a cardiac rhythm management device, for example.

Next, in operation 704, the information obtained from operations 700 and702 (if performed) is analyzed to determine whether a cardiac event ofinterest is occurring. For example, the information may be analyzed todetermine whether ischemia or acute heart failure decompensation isbeing exhibited by a patient. If no such event is detected, control isreturned to operation 700, and the monitoring continues. On the otherhand, if such an event is detected, control is passed to operation 706.

Operation 706 is optional. In operation 706, occurrence of the detectedevent is communicated. The communication may occur between an implantedcardiac management device (performing operations 700-706) and aprogrammer, a personal digital assistant, an access point to a network,such as a wireless or wired network, or to a wireless communicationdevice that may forward the message to an access point for communicationto a remote computing system, for example. (The programmer or personaldigital assistant may relay such a message to a remote computing).Alternatively, the communication may occur between the detection routineexecuting on the internal controller and a history logging routineexecuted by the same internal controller. Thus, the occurrence of thedetected event is logged, so that a health care professional may becomeaware of the event, for example, the next time he or she reads the datacontained in the log. After execution of operation 706, control isreturned to operation 700, and monitoring continues.

The method of FIG. 7 may be performed continually or at intervals. Forexample, a patient may be monitored for a given cardiac condition onceper day (e.g., at night) or several times each day, meaning that themethod of FIG. 7 would be executed once per day or several times perday.

Closed-Loop Titration System

As explained previously herein, titration of a drug to a patient caninfluence performance of the patient's heart. For example, an inotropicagent can improve contractility of the heart. Inotropes can be used tomanage patient symptoms of advanced heart failure or HF patients (e.g.,New York Heart Association or NYHA class IV patients). These patientsare refractory to oral agents and intravenous (IV) therapy is typicallyused to prevent pulmonary edema and deterioration of the patient'shemodynamic system.

Home intravenous inotropic therapy (HT) is not only associated withimproved status of hemodynamic function, decreased hospital admissions,and decreased length of hospital stay, but also with a reduction in costof treatment. Briefly, HT therapy can involve establishing an IV accessusing a catheter (e.g., a catheter for percutaneous central access, or aHickman catheter if long-term access is needed) and delivery ofinotropic agents such as dobutamine or milrinone either continuously orintermittently over two to three days per week. If the patient is fluidvolume overloaded, diuretic agents may also be provided by IV incombination with inotropes.

HT can be labor intensive (e.g., requiring home nurse assistance), andwith HT the physician may receive limited data on the patient'streatment. Qualification for coverage for health care assistance (e.g.,Medicare) may require criteria such as close monitoring of the“patient's cardiac symptoms, vital signs, weight, lab values, andresponse to therapy.” Instead of a manually administering HT, aclosed-loop sensor-based medical system may be a more cost-effectiveapproach for meeting these criteria. The ability to titrate drug therapybased on physiological sensor data may also reduce drug adverse effectsand mortality, or alternatively be more effective at weaning the patientoff inotropes for destination therapy.

Implantable CRM devices and subcutaneous diagnostic devices are oftenindicated for HF patients. As explained previously herein, these devicescan include implantable sensors (e.g., a heart sound sensor). Theseimplantable sensors can be part of a drug infusion system thatautomatically provides IV therapy to the patient at the patient's home.Measurements provided by these sensors can be used to adjust the IVtherapy and thereby provide a closed-loop titration system. A home-basedclosed-loop titration system can provide greater patient convenience andprovide the clinician with the ability to remotely monitor safety andeffectiveness of HT. Typical external titration devices used for HT donot use physiologic information of the patient to control titration ofthe drug. This may be due to the complexity that such a device wouldentail. The variety of cardiothoracic measurements provided usingimplanted sensing devices are ideally suited for control of inotropesand diuretics for home-based decongestive therapy for the treatment ofadvanced heart failure.

FIG. 8 shows a flow diagram of an example of a method of operating amedical device or medical device system to provide closed-loop controlof titration of an agent for decongestive therapy. Any of the operationsshown in FIG. 8 may be performed by a control circuit such as thecontroller shown in FIG. 5.

At operation 800, one or more sensed physiological signals are generatedusing one or more physiological sensing circuits. A physiological sensorsignal includes physiological information about the patient. Forexample, a physiological sensor circuit may provide information aboutthe hemodynamic system of the patient or subject. At least one of thephysiological sensing circuits is implantable. As an example, theimplantable physiological sensing circuit can include an implantableheart sound sensing circuit that provides an electrical heart soundsignal, such as a signal that provides an indication of heart soundamplitude versus time for example. Other examples of the implantablephysiological sensing circuit are described herein.

At operation 802, one or more physiological parameters of a subject arerecurrently measured using the one or more sensed physiological signals.The physiological parameters indicate a status of heart failure of thepatient. For example, a measure of the amplitude of the S1 heart soundprovides an indication of the contractility of patient's heart. Lower S1amplitudes are associated with more severe cases of HF.

At operation 804, the one or more measured physiological parameters arecompared to one or more physical parameter targets. For example, themeasured amplitude of the S1 heart sound can be compared to a target S1amplitude value, a target range of S1 amplitude values, or a S1amplitude target threshold value. The comparison can be made by a devicethat provides drug therapy to treat HF (e.g., a device that controltitration of an inotropic agent to the patient).

At operation 806, drug therapy provided to the patient is recurrentlyadjusted by drug therapy device according to the comparison of themeasured physiological parameters to the physiological parametertargets. For example, the device may cause a bolus of an inotropic agentto be delivered to the patient if the amplitude of the S1 heart sounddoes not satisfy a specified (e.g., programmed) amplitude thresholdvalue.

FIG. 9 shows a block diagram of portions of an example of a system 900that provides closed-loop control of titration of an agent fordecongestive therapy. The system 900 includes one or more physiologicalsensing circuits 905 i-905 n. A physiological sensing circuit generatesa sensed physiological signal and at least one of the physiologicalsensing circuits is implantable. The system 900 also includes ameasurement circuit 910, a comparison circuit 915, a therapy circuit 920and a control circuit 925. The measurement circuit 910 recurrentlymeasures one or more physiological parameters of a subject using one ormore of the sensed physiological signals. The measured physiologicalparameters indicate a status of heart failure of the subject.

The therapy circuit 920 controls delivery of one or more drugs to treatheart failure. The therapy circuit 920 may control delivery of a drugfrom a reservoir included in a medical device (e.g., a device such as adrug pump that is implantable subcutaneously), or the therapy circuit920 may control delivery of the drug from a source external to thedevice (e.g., through control of an IV drug delivery sub-system). Thetherapy circuit 920 may control titration of at least one of aninotropic agent, a diuretic agent, an aquaretic agent, or a vasodilatingagent. If the therapy circuit 920 controls an IV drug deliverysub-system, the therapy circuit may control titration of at least one ofa crystalloid (e.g., saline, lactated ringers etc.) or a colloid to thepatient. The comparison circuit 915 compares the one or morephysiological parameter measurements provided by the measurement circuit910 to one or more physiological parameter target values.

The control circuit 925 is in electrical communication with thecomparison circuit 915 and the therapy circuit 920. The electricalcommunication allows signals to be communicated among the controlcircuit 925, the comparison circuit 915 and the therapy circuit 920 eventhough there may be intervening circuitry between the circuits. Thecontrol circuit 925 recurrently adjusts delivery of drug therapy to thesubject according to the comparison of the measured physiologicalparameters to the physiological parameter targets. Thus, the system 900provides device-based closed-loop system control of the drug therapyprovided to the patient.

The control circuit 925 may perform a closed-loop algorithm thatcombines information from the physiological sensing circuits, andadjusts the drug infusion rate to influence or control the values of thephysiological parameters. The control circuit 925 may adjust the druginfusion provided by the therapy circuit 920 using a “control toparameter range” approach, where the closed-loop algorithm changes oneor more of the rate of drug infusion, a total daily infusion dose, and adrug infusion schedule (e.g., from once a day to twice a day, from twicea day to three times a day, etc.) to meet a target range of values for aphysiological parameter. The control circuit 925 may adjust the druginfusion provided by the therapy circuit 920 using a “control to target”approach, where the closed-loop algorithm increases or decreases therate of drug infusion to move a value of a physiological parametertoward a target value. The control circuit 925 may adjust the druginfusion provided by the therapy circuit 920 using “ON/OFF control,”where the closed-loop algorithm initiates drug infusion when aphysiological parameter does not satisfy a physiological parameterthreshold value and stops the drug infusion when the physiologicalparameter satisfies the physiological parameter threshold value.

The response of the patient to the drug can be viewed as a “plant model”in control theory. The control circuit 925 may implement a proportionalcontroller, a proportional integral controller, or a proportionalintegral derivative controller to control the drug infusion. In a simpleproportional controller, the controller output is proportional to theerror in a measurement of the parameter of interest, where the error isdefined as the difference between the target value of the parameter ofinterest and the measured value of the parameter. A proportionalintegral (PI) control algorithm is designed to eliminate an offsetassociated with the proportional controller by making the controlleroutput proportional to the amount of time the error is present. In aproportional integral derivative (PID) controller, derivative action isadded to increase the speed of response and to anticipate changes. Thederivative term acts on the rate of change of the error.

The inputs for the closed-loop algorithm may incorporate supervisoryinput from a clinician and the patient as well as the output from thephysiological sensing circuits. The output of the closed-loop algorithmcan be a profile for the drug infusion. The profile can be the rate ofdrug infusion or an amount of drug infused versus time. The feedback ofthe output can be a characterization of the hemodynamic response (e.g.,a short term response, step response, impulse response, etc.) of thepatient.

The physiological sensing circuits may be included in a combination ofimplantable and external devices and the system 900 may be a combinationof implantable and external devices. A significant proportion of HFpatients are prescribed implantable CRM devices because cardiacarrhythmias often cause adverse events in patients with advanced HF. Insome examples, a CRM device implanted in the patient may include theimplantable physiological sensing circuit, and an external device mayinclude the control circuit 925, the comparison circuit 915, themeasurement circuit 910, the therapy circuit 920 and an externalphysiological sensing circuit.

Implantable physiological sensing circuits may provide the advantage ofallowing more frequent measurements of the physiological parameters,including both acute measurements of the parameters during drug infusionand chronic measurements of the parameters between infusions of thedrug. One or both of acute measurements and chronic measurements of thephysiological parameter can be used by the closed-loop algorithm totailor drug therapy to the needs of the patient.

In some examples, the physiological sensing circuits 905 i-905 n caninclude an implantable heart sound sensing circuit. The heart soundsensing circuit generates a sensed heart sound signal. The heart soundsignal can be an electrical signal representative of mechanical activityof the heart of the patient. Examples of a heart sound sensing circuitinclude an accelerometer and a microphone.

The physiological parameter measured by measurement circuit 910 of FIG.9 may include a measure a magnitude of a heart sound (e.g., one or moreof the S1, S2, S3 and S4 heart sounds). The measured physiologicalparameter is compared to a target value (e.g., the measured absolutemagnitude value of the S1 heart sound is compared to a specifiedmagnitude target value). The measured physiological parameter mayinclude a time interval between a first heart sound signal feature and asecond heart sound signal feature. Some examples of the interval includethe interval between an S1 and S2 heart sound (e.g., the heart soundbased ejection time or HSET). The control circuit 925 adjusts deliveryof the drug therapy according to a comparison of the least one of themagnitude or the time interval measured in the heart sound signal to atleast one of a target heart sound magnitude value or a time intervaltarget value.

In some examples, the physiological sensing circuits include animplantable pressure sensing circuit that generates a sensed pressuresignal. The pressure signal can be representative of at least one ofarterial blood pressure, central venous pressure, pulmonary arterypressure, left atrial pressure, or abdominal pressure of the patient.The measurement circuit 910 provides, as the physiological parameter, ameasure of at least one of arterial blood pressure, central venouspressure, pulmonary artery pressure, left atrial pressure, or abdominalpressure using the sensed pressure signal. The comparison circuit 915provides an indication of an outcome of at least one of: a comparison ofa measure of arterial blood pressure to a target arterial bloodpressure, a comparison of a measure of central venous pressure to atarget central venous pressure value, a comparison of a measure ofpulmonary artery pressure to a target pulmonary artery pressure, acomparison of a measure of left atrial pressure to a target left atrialpressure value, or a comparison of a measure of abdominal pressure to atarget value of abdominal pressure. The control circuit 925 recurrentlyadjusts delivery of the drug therapy according to the comparison.

In some examples, the physiological sensing circuits include animplantable cardiac activity sensing circuit (e.g., a cardiac signalsense amplifier) that generates a cardiac activity signal. Themeasurement circuit 910 provides, as the physiological parameter, ameasure of heart rate of the patient. The comparison circuit 915provides an indication of an outcome of a comparison of the heart rateof the subject to a target heart rate value. In some examples, thephysiological sensing circuits include an implantable physical activitysensing circuit in addition to the implantable cardiac activity sensingcircuit. The implantable physical activity sensing circuit generates aphysical activity signal representative of physical activity of thesubject. Some examples of implantable physical activity sensing circuitinclude an accelerometer and a vibration sensor. The measurement circuit910 provides, as the physiological parameter, a measure of physiologicalresponse to activity of the patient (e.g., a change in heart rate orchange in cardiac depolarization interval in response to a change inactivity level). The comparison circuit 915 provides an indication of anoutcome of a comparison of the measure of physiologic response toactivity to a physiological response to activity target.

In some examples, the physiological sensing circuits include animplantable heart sound sensing circuit as described previously herein,and an electrogram circuit that generates a sensed electrogram signal orwaveform. An electrogram signal is a sampled cardiac activity signalthat can be sensed using implantable or subcutaneous electrodes and acardiac signal sense amplifier. The electrogram signal is representativeof electrical activity of the heart. The measurement circuit 910 mayprovide, as the physiological parameter, a time interval between afeature detected in the sensed heart sound signal and a feature detectedin the sensed electrogram signal. Some examples include an intervalbetween an R-wave feature (e.g., an R-wave peak) in the electrogramsignal and an S1 heart sound feature (e.g., an onset of the S1 heartsound) in the heart sound signal (i.e., the heart sound basedpre-ejection period or HSPEP), an interval between a Q-wave feature inthe electrogram signal and an S1 heart sound feature in the heart soundsignal (Q-S1 interval), an interval between an R-wave feature in theelectrogram signal and an S2 heart sound feature (e.g., an onset of theS2 heart sound) in the heart sound signal (R-S2 interval), and aninterval between a Q-wave feature in the electrogram signal and an S2heart sound feature in the heart sound signal (Q-S2 interval). Thecontrol circuit 925 adjusts delivery of the drug therapy according to acomparison of the measured time interval to a time interval targetvalue.

In some examples, the physiological sensing circuits include arespiration sensing circuit. The respiration sensing circuit may providean electrical “respiration signal” that includes respirationinformation. The respiration sensing circuit may be implantable orexternal. An example of a respiration sensing circuit includes animplantable impedance sensing circuit, and the respiration signal may bea measured impedance signal. An example of an implantable impedancesensing circuit is an implantable transthoracic impedance sensingcircuit. Transthoracic impedance can be sensed between an electrode onan implantable lead and an electrode formed on a housing of an IMD. Anapproach to measuring thoracic impedance is described in Hartley et al.,U.S. Pat. No. 6,076,015 “Rate Adaptive Cardiac Rhythm Management DeviceUsing Transthoracic Impedance,” filed Feb. 27, 1998, which isincorporated herein by reference. Another example of the respirationsensing circuit includes a motion sensing circuit (e.g., anaccelerometer) that senses motion of the thoracic cavity of the subject.The motion sensing circuit may implantable or external. Another exampleof the respiration sensing circuit respiration circuit includes a volumeor flow sensor.

The measurement circuit 910 may extract one or more respirationparameters from the respiration signal. Some examples of a respirationparameter include a respiration rate of the subject, an inter-breathinterval of the subject, a measure of variability of respiration rate ofthe subject, or a measure of variability of an inter-breath interval ofthe subject. Additional examples of a respiration parameter includetidal volume and minute ventilation calculated for the patient. Incertain examples, the measurement circuit 910 can extract respirationrate from the respiration signal and determine tidal volume from themeasured impedance values of the respiration signal. Minute ventilationcan then be calculated using the respiration rate and tidal volume asMV=RR×TV. The comparison circuit 915 provides an indication of anoutcome of a comparison of the measured respiration parameter to arespiration parameter target value.

In some examples, the physiological sensing circuits include animplantable impedance circuit that generates an impedance signalrepresentative of intra-thoracic impedance of the patient.Intra-thoracic impedance can be sensed between an electrode on animplantable lead and an electrode formed on a housing of an IMD. Ameasure of intra-thoracic impedance can be useful as a surrogate measureof fluid buildup in the thorax region of the patient. The measurementcircuit 910 provides a measure of intra-thoracic impedance and thecomparison circuit 915 provides an indication of a comparison of themeasure of intra-thoracic impedance to a target intra-thoracic impedancevalue.

In some examples, the physiological sensing circuits include animplantable impedance circuit that generates an impedance signalrepresentative of intracardiac impedance of the patient. An intracardiacimpedance sensing circuit may include electrodes placed within a chamberof the heart and provide an “intracardiac impedance signal”representative of intracardiac impedance versus time. The electrodes maybe placed in a right ventricle of the heart and the measuredintracardiac impedance waveform can be signal processed to obtain ameasure of the time interval beginning with a paced or spontaneous QRScomplex (systole marker) and ending with a point where the impedancesignal crosses the zero axis in the positive direction following the QRScomplex. The resulting time interval is inversely proportional to thecontractility of the heart. Systems and methods to measure intracardiacimpedance are described in Citak et al., U.S. Pat. No. 4,773,401,entitled “Physiologic Control of Pacemaker Rate Using Pre-EjectionInterval as the Controlling Parameter,” filed Aug. 21, 1987, which isincorporated herein by reference in its entirety. The measurementcircuit 910 can provide a measure of intracardiac impedance and thecomparison circuit 915 can provide an indication of a comparison of themeasure of intracardiac impedance to a target intracardiac impedancevalue.

In some examples, the physiological sensing circuits include animplantable sensing circuit that generates a physiological signalindicative of a level of a biochemical analyte present in the patient.Some examples of biochemical analytes include sodium, potassium,chromium, blood urea nitrogen (BUN), hematocrit, and hemoglobin. Themeasurement circuit 910 provides an indication of the level of thebiochemical analyte, and the comparison circuit 915 provides anindication of outcome of a comparison of the indicated level ofbiochemical analyte to a target level of the biochemical analyte.

As explained previously herein, the system 900 of FIG. 9 can include acombination of implantable and external devices. External sensingcircuits may be used to measure physiological parameters that cannoteffectively be measured using implantable sensors. In some examples, theone or more physiological sensing circuits 905 i-905 n include at leastone implantable physiological sensing circuit that provides a firstsensed physiological signal, and at least one external sensing circuitconfigured to provide a second sensed physiological signal.

Some examples of an external sensing circuit include one or more devicesthat provide an indication of the patient's weight, arterial bloodpressure and peripheral edema. Additional examples include externaldevices that provide point-of-care measurements of biochemical analytessuch as brain natriuretic peptide or BNP (including an N-terminal aminoacid secreted with BNP or NT-Pro-BNP), creatinine, urinalysis, etc. Themeasurements may be obtained using the same access site used forinfusion of the drug. Further examples of external sensing circuitsinclude external versions of the implantable sensing circuits describedpreviously herein, such as a respiration sensing circuit, a heart soundsensing circuit, and a thoracic impedance sensing circuit.

The second sensed physiological signal provided by the external sensingcircuit can be representative of at least one of weight of the patient,respiration of the patient, a heart sound of the patient, arterial bloodpressure of the patient, an indication of peripheral edema of thepatient, thoracic fluid present in the patient, or a level ofbiochemical analyte present in the patient.

The measurement circuit 910 provides a measure of a first physiologicalparameter using the first sensed physiological signal and a secondphysiological parameter using the second sensed physiological signal.The second physiological parameter includes at least one of a measuredweight of the patient, a respiration parameter of the patient, amagnitude of a heart sound, a time interval between a first heart soundsignal feature and a second heart sound signal feature, a measuredarterial blood pressure of the patient, a measure of edema of thepatient, or an indication of a level of biochemical analyte present inthe patient.

The comparison circuit provides an indication of an outcome of acomparison of the first physiological parameter to a target firstphysiological parameter value and the second physiological parameter toa target second physiological parameter value. The control circuit 925adjusts delivery of the drug therapy according to the outcome of thecomparison of the first and second physiological parameters to thetarget first and second physiological parameter values.

In some examples, the measurement circuit 910, the comparison circuit915, the therapy circuit 920, the control circuit 925 and at least oneimplantable physiological sensor are included in an implantable device.The implantable device can include a drug reservoir or drug pump, andthe therapy circuit 920 controls delivery of drug therapy from the drugpump or reservoir. The implantable device may communicate wirelesslywith an external device that provides one or both of a physiologicalsignal sensed by the external device and a physiological parameterextracted from the sensed physiological signal. The implantable devicemay provide electrical cardiac therapy such as cardiac resynchronizationtherapy (CRT) for example. Thus, both the electrical cardiac therapy andthe drug therapy can be an output of the closed-loop feedback systemimplemented by the system 900 to control one or more physiologicalparameters.

FIG. 10 shows a block diagram of portions of another example of a system1000 that provides closed-loop control of titration of an agent fordecongestive therapy. The system 1000 includes an external device 1007and an implantable device 1003. The external device 1007 includes atherapy circuit 1020 that controls delivery of one or more drugs totreat heart failure, and includes an external physiological sensingcircuit 1005A.

The implantable device 1003 includes at least one implantablephysiological sensing circuit 1005B. The external physiological sensingcircuit 1005A and implantable physiological sensing circuit 1005B eachprovide a physiological signal such as the physiological signalsdescribed herein. The implantable device 1003 and the external device1007 include communication circuits 1055 and 1030 respectively tocommunicate information between the implantable device 1003 and theexternal device 1007. The communication is wireless and may include RFcommunication or inductive telemetry.

The implantable device may communicate a representation (e.g., adigitized representation) of the physiological signal sensed by theimplantable physiological sensing circuit 1005B to the external device1007. The external device 1007 includes a measurement circuit 1010 thatrecurrently measures one or more physiological parameters using one ormore of the physiological signals sensed by the external physiologicalsensing circuit 1005A and implantable physiological sensing circuit1005B. In some examples, the implantable device 1003 includes ameasurement circuit 1035 that measures a physiological parameter usingthe physiological signal sensed by the implantable physiological sensingcircuit 105B and communicates a measured physiological parameter to theexternal device 1007.

The external device 1007 includes a comparison circuit 1015 thatcompares the one or more physiological parameter measurements to one ormore physiological parameter target values. The external device 1007also includes a control circuit 1025 that recurrently adjusts deliveryof drug therapy to the patient according to the comparison of themeasured physiological parameters to the physiological parametertargets.

In some examples, the implantable device 1003 includes a therapy circuit1040 that provides electrical cardiac therapy to the patient, such ascardiac resynchronization therapy for example. According to thecomparison of the measured physiological parameters to the physiologicalparameter targets by the comparison circuit 1015 of the external device1007, the control circuit 1025 may communicate an indication to initiateor adjust the electrical cardiac therapy delivered by the implantabledevice 1003. The implantable device 1003 may include a control circuit1045 to manage the electrical cardiac therapy. Thus, the electricalcardiac therapy provided by the implantable device 1003 can be part ofthe closed-loop feedback system implemented by the system 1000.

The therapy circuit 1020 of external device 1007 may control intravenousdelivery of the drug therapy to the patient (e.g., the external devicemay be an IV drug infusion system). The external device may include auser interface 1050 to receive input from the patient to include patientphysiology in the control of the drug therapy. For instance, the userinterface 1050 may include a visual analog scale to test the response ofthe patient. The response may be captured by the external device 1007and incorporated into the control algorithm implemented by the controlcircuit 1025.

In some examples, the external device 1007 is able to communicate with aremote third device using the communication circuit 1030 or a separatecommunication circuit. The third device may be a remote monitoringsystem that provides patient monitoring and management of patientcardiac disease. The communication between the external device and theremote system may be RF communication via a local or person areanetwork, or the communication may be via a more extensive communicationnetwork such as the internet or a cellular phone network. The remotemonitoring system may receive physiological information and a drugtherapy delivery profile from the external device 1007 and display theinformation to a physician or include the information in a report forreview by a physician.

The examples of closed-loop drug titration devices, methods and systemsprovided herein can make full use of all the physiological informationavailable regarding the patient. The systems can be implemented in thepatient's home and thus provide greater patient convenience. They alsoallow give the clinician the ability to remotely monitor safety andeffectiveness of HT. Closed-loop drug therapy may improve patienttreatment at lower cost.

Additional Notes

Embodiments of the invention may be implemented in one or a combinationof hardware, firmware, and software. Embodiments of the invention mayalso be implemented as instructions stored on a machine-readable medium,which may be read and executed by at least one processor to perform theoperations described herein. A machine-readable medium may include anymechanism for storing or transmitting information in a form readable bya machine (e.g., a computer). For example, a machine-readable medium mayinclude read-only memory (ROM), random-access memory (RAM), magneticdisc storage media, optical storage media, flash-memory devices,electrical, optical, acoustical or other form of propagated signals(e.g., carrier waves, infrared signals, digital signals, etc.), andothers.

The Abstract is provided to comply with 37 C.F.R. Section 1.72(b)requiring an abstract that will allow the reader to ascertain the natureand gist of the technical disclosure. It is submitted with theunderstanding that it will not be used to limit or interpret the scopeor meaning of the claims.

In the foregoing detailed description, various features are occasionallygrouped together in a single embodiment for the purpose of streamliningthe disclosure. This method of disclosure is not to be interpreted asreflecting an intention that the claimed embodiments of the subjectmatter require more features than are expressly recited in each claim.Rather, as the following claims reflect, inventive subject matter liesin less than all features of a single disclosed embodiment. Thus, thefollowing claims are hereby incorporated into the detailed description,with each claim standing on its own as a separate preferred embodiment.

The claimed invention is:
 1. An apparatus comprising: one or morephysiological sensing circuits including an implantable sensing circuitand an external sensing circuit, wherein the implantable physiologicalsensing circuit is configured to provide a first sensed physiologicalsignal and the external sensing circuit is configured to provide asecond sensed physiological signal, wherein the second sensedphysiological signal is representative of at least one of: weight of thesubject, respiration of the subject, a heart sound of the subject,arterial blood pressure of the subject, an indication of peripheraledema of the subject, thoracic fluid present in the subject, or a levelof biochemical analyte present in the subject; a measurement circuitconfigured to recurrently measure one or more physiological parametersof a subject that indicate a status of heart failure of the subject,including a first physiological parameter using the first sensedphysiological signal and a second physiological parameter using thesecond sensed physiological signal, wherein the second physiologicalparameter includes at least one of a measured weight of the subject, arespiration parameter of the subject, a magnitude of a heart sound, atime interval between a first heart sound signal feature and a secondheart sound signal feature, a measured arterial blood pressure of thesubject, a measure of edema of the subject, or an indication of a levelof biochemical analyte present in the subject; a comparison circuitconfigured to compare the first physiological parameter to a targetfirst physiological parameter value and the second physiologicalparameter to a target second physiological parameter value and providean indication of an outcome of a comparison; a therapy circuitconfigured to control delivery of one or more drugs to treat heartfailure; and a control circuit in electrical communication with thecomparison circuit and the therapy circuit and configured to adjustdelivery of the drug therapy according to the outcome of the comparisonof the first and second physiological parameters to the target first andsecond physiological parameter values.
 2. The apparatus of claim 1,wherein the one or more physiological sensing circuits includes a heartsound sensing circuit configured to generate a sensed heart soundsignal, wherein the heart sound signal is representative of mechanicalactivity of the heart of the subject, wherein the measurement circuit isconfigured to measure at least one of a magnitude of a heart sound or atime interval between a first heart sound signal feature and a secondheart sound signal feature, and wherein the control circuit isconfigured to adjust delivery of the drug therapy according to acomparison of the least one of the measured magnitude or the measuredtime interval to at least one of a target heart sound magnitude value ora time interval target value.
 3. The apparatus of claim 1, wherein thetherapy circuit is configured to control titration of an inotropic agentto the subject.
 4. The apparatus of claim 1, wherein the therapy circuitis configured to control titration of at least one of a diuretic agent,an aquaretic agent, or a vasodilating agent to the subject according tothe comparison.
 5. The apparatus of claim 1, wherein the therapy circuitis configured to control delivery of at least one of a crystalloid or acolloid to the subject according to the comparison.
 6. The apparatus ofclaim 1, wherein the one or more physiological sensing circuits includesan implantable pressure sensing circuit configured to generate a sensedpressure signal, wherein the pressure signal is representative of atleast one of arterial blood pressure, central, venous pressure,pulmonary artery pressure, left atrial pressure, or abdominal pressureof the subject, wherein the measurement circuit is configured to providea measure of at least one of arterial blood pressure, central venouspressure, pulmonary artery pressure, left atrial pressure, or abdominalpressure using the sensed pressure signal, and wherein the comparisoncircuit is configured to provide an indication of an outcome of at leastone of: a comparison of a measure of arterial blood pressure to a targetarterial blood pressure, a comparison of a measure of central venouspressure to a target central venous pressure value, a comparison of ameasure of pulmonary artery pressure to a target pulmonary arterypressure, a comparison of a measure of left atrial pressure to a targetleft atrial pressure value, or a comparison of a measure of abdominalpressure to a target value of abdominal pressure, and wherein thecontrol circuit is configured to recurrently adjust delivery of the drugtherapy according to the at least one comparison.
 7. The apparatus ofclaim 1, wherein the one or more physiological sensing circuits includesan implantable cardiac activity sensing circuit configured to generate acardiac activity signal and an implantable physical activity sensingcircuit configured to generate a physical activity signal representativeof physical activity of the subject, wherein the measurement circuit isconfigured to provide a measure of at least one of a heart rate of thesubject or a physiological response to activity of the subject, andwherein the comparison circuit is configured to provide an indication ofan outcome of at least one of: a comparison of the heart rate of thesubject to a target heart rate value, or a comparison of the measure ofphysiologic response to activity to a physiological response target. 8.The apparatus of claim 1, wherein the one or more physiological sensingcircuits includes at least one of an implantable respiration sensingcircuit configured to generate a respiration signal representative ofrespiration of the subject, or an implantable impedance circuitconfigured to generate at least one of an impedance signalrepresentative of intra-thoracic impedance of the subject or animpedance signal representative of intracardiac impedance of thesubject, wherein the measurement circuit is configured to provide atleast one of: a measure of a respiration parameter, a measure ofintra-thoracic impedance, or a measure of intracardiac impedance, andwherein the comparison circuit is configured to provide an indication ofan outcome of at least one of: a comparison of the measured respirationparameter to a respiration parameter target value, a comparison of themeasure of intra-thoracic impedance to a target intra-thoracic impedancevalue, or a comparison of the measure of intracardiac impedance to atarget intracardiac impedance value.
 9. The apparatus of claim 1,including an external device and an implantable device, wherein thecomparison circuit, the therapy circuit and the control circuit areincluded in the external device, and the implantable device isconfigured to communicate the measure of the one or more physiologicalparameters to the external device.
 10. The apparatus of claim 9, whereinthe implantable device includes a second therapy circuit configured toprovide electrical cardiac therapy to the heart of the subject, whereinthe control circuit is configured to initiate delivery of electricalcardiac therapy according to the comparison of the measuredphysiological parameters to the physiological parameter targets.
 11. Theapparatus of claim 1, wherein the measurement circuit, the comparisoncircuit, the therapy circuit, the control circuit and the at least oneimplantable physiological sensor are included in an implantable device.12. The apparatus of claim 1, wherein the one or more physiologicalsensing circuits includes a heart sound sensing circuit configured togenerate a sensed heart sound signal and a cardiac electrogram sensingcircuit configured to generate a sensed cardiac electrogram signal,wherein the electrogram signal is representative of electrical activityof the heart of the subject, wherein the measurement circuit isconfigured to measure a time interval between a feature of theelectrogram signal and a feature of the heart sound signal, and whereinthe control circuit is configured to adjust delivery of the drug therapyaccording to a comparison of the measured time interval to a timeinterval target value.
 13. A method comprising: generating at least afirst sensed physiological signal using an implantable physiologicalsensing circuit and at least a second sensed physiological signal usingan external sensing circuit, wherein the external sensing circuitprovides a physiological signal representative of at least one of aweight of the subject, arterial blood pressure of the subject, a measureof peripheral edema of the subject, or a level of biochemical analytepresent in the subject; measuring at least a first physiologicalparameter indicative of a status of heart failure of the subject usingthe first sensed physiological signal and at least a secondphysiological parameter using the second sensed physiological signal,wherein the second physiological parameter includes at least one of ameasured weight of the subject, a measured arterial blood pressure ofthe subject, a measure of peripheral edema of the subject, or a measureof a level of biochemical analyte present in the subject; comparing thefirst physiological parameter to a target first physiological parametervalue and comparing the second physiological parameter to a targetsecond physiological parameter value using a device that provides a drugtherapy to treat heart failure; and recurrently adjusting a drug therapyaccording to the comparison of the first and second physiologicalparameters to the target first and second physiological parametervalues.
 14. The method of claim 13, wherein generating at least a firstand second sensed physiological signals includes generating a heartsound signal using an implantable heart sound sensing circuit, whereinthe heart sound signal is representative of mechanical activity of theheart of the subject, and wherein measuring at least a first and secondphysiological parameters includes measuring at least one of: a magnitudeof a heart sound and adjusting drug therapy includes adjusting the drugtherapy according to a comparison of the parameter to a target heartsound magnitude value; or a time interval between a first heart soundsignal feature and a second heart sound signal feature and adjustingdrug therapy includes adjusting the drug therapy according to acomparison of the parameter to a time interval target value.
 15. Themethod of claim 13, wherein recurrently adjusting drug therapy includesadjusting device-based titration of an inotropic agent to the subjectaccording to the comparison, and wherein the method further includesrecurrently adjusting device-based electrical cardiac therapy accordingto the comparison of the measured physiological parameters to thephysiological parameter targets.
 16. The method of claim 13, whereingenerating at least a first and second sensed physiological signalsincludes generating a pressure signal generated using an implantablepressure sensing circuit, wherein the pressure signal is representativeof at least one of arterial blood pressure, central venous pressure,pulmonary artery pressure, left atrial pressure, or abdominal pressureof the subject, and wherein comparing the measured physiologicalparameters to one or more physiological parameter targets includes atleast one of comparing a measure of arterial blood pressure to a targetarterial blood pressure, comparing a measure of central venous pressureto a target central venous pressure value, comparing a measure ofpulmonary artery pressure to a target pulmonary artery pressure,comparing a measure of left atrial pressure to a target left atrialpressure value, or comparing a measure of abdominal pressure to a targetvalue of abdominal pressure.
 17. The method of claim 13, whereingenerating at least a first and second sensed physiological signalsincludes at least one of: generating a cardiac activity signal using animplantable cardiac signal sensing circuit or generating a physicalactivity signal representative of physical activity of the subject usingan implantable physical activity sensing circuit, wherein measuring atleast a first and second physiological parameters includes measuring atleast one of heart rate of the subject or physiological response toactivity of the subject, and wherein comparing the measuredphysiological parameters to physiological parameter targets includescomparing the heart rate of the subject to a target heart rate value orcomparing the physiologic response of the subject to activity to aphysiological response target.
 18. An apparatus comprising: one or morephysiological sensing circuits configured to generate a sensedphysiological signal that includes physiological information, andwherein at least one of the physiological sensing circuits includes animplantable sensing circuit configured to generate a physiologicalsignal indicative of a level of a biochemical analyte present in thesubject, a measurement circuit configured to recurrently measure one ormore physiological parameters of a subject using one or more of thesensed physiological signals including the level of biochemical analyte,wherein the one or more physiological parameters indicate a status ofheart failure of the subject; a comparison circuit configured to comparethe one or more physiological parameter measurements to one or morephysiological parameter target values and provide an indication of anoutcome of a comparison of the indicated level of biochemical analyte toa target level of the biochemical analyte; a therapy circuit configuredto control delivery of one or more drugs to treat heart failure; and acontrol circuit in electrical communication with the comparison circuitand the therapy circuit and configured to recurrently adjust delivery ofdrug therapy according to the comparison of the measured physiologicalparameters to the physiological parameter targets.